6-lower alkyl-a-nor-delta**5-androstene and-delta**5,9(11) androstadiene - 17 - carboxylic acid halides

ABSTRACT

1-(A-CO-),3A,8A,10A-TRI(CH3-),5-X,6-(O=),9-R,9-R&#39;&#39;-   1,2,3,3A,3B,4,6,7,8,8A,8B,9,10,10A-   TETRADECAHYDRODICYCLOPENTA(A,F)NAPHTHALENE,   1-(A-CO-),3A,8A,10A-TRI(CH3-),5-X,6-(O=)-   1,2,3,3A,3B,4,6,7,8,8A,8B,9,10,10A-   TETRADECAHYDRODICYCLOPENTA(A,F)NAPHTHALENE,   1-(A-CO-),3,6-DI(O=),3A,8A,10A-TRI(CH3-),5-X,9-R,9-R&#39;&#39;-   1,2,3,3A,3B,4,6,7,8,8A,8B,9,10,10A-   TETRADECAHYDRODICYCLOPENTA(A,F)NAPHTHALENE,   1-(A-CO-),3,6-DI(O=),3A,8A,10A-TRI(CH3-),5-X-   1,2,3,3A,3B,4,6,7,8,8A,8B,9,10,10A-   TETRADECAHYDRODICYCLOPENTA(A,F)NAPHTHALENE   WHEREIN A IS HALOGEN; R IS HYDROGEN; R&#39;&#39; IS HYDROXY; AND TOGETHER R AND R&#39;&#39; IS OXO; AND X IS LOWER ALKYL. THESE COMPOUNDS ARE USEFUL AS CHEMICAL INTERMEDIATES IN MAKING COMPOUNDS WHICH POSSES ANTI-ANDROGENIC ACITIVITY. THIS INVENTION RELATES TO COMPOUNDS OF THE FORMULAE

United States Patent ()1 hoe 3,567,774 Patented Mar. 2, 1971 the Public Int. Cl. C07c 63/44 U.S. Cl. 260-544 1 Claim ABSTRACT OF THE DISCLOSURE This invention relates to compounds of the formulae ris I CH3 GOA wherein A is halogen; R is hydrogen; R is hydroxy; and together R and R is 0x0; and X is lower alkyl. These compounds are useful as chemical intermediates in making compounds which possess anti-androgenic activity.

CHzZ

I CHzZ (II -O g=0 ms 6H,

CHzZ CH2Z 1 0:0 =0 R 1 R and W I wherein R is hydrogen; R is hydroxy; and together R and R is oxo (0:); X is lower alkyl (e.g. methyl) and Z is selected from the group consisting of hydrogen, hydroxy, acyloxy and halogen (e.g. chloro, fluoro, bromo or iodo).

The preferred acyloxy radicals are those of hydrocarbon carboxylic acids of less than twelve carbon atoms, as exemplified by the lower alkanoic acids (eg. acetic, propionic, butyric and tert.-pentanoic acid), the lower alkenoic acids, the monocyclic aryl carboxylic acids (e.g. benzoic and toluic acid), the monocyclic aryl lower alkanoic acids (e.g. phenacetic and fl-phenylpropionic acid), the cycloalkane carboxylic acids and the cycloalkene carboxylic acids.

The products of this invention are physiologically active compounds which possess antiandrogenic activity and thus may be employed in the treatment of hyperandrogenie acne, for which purposes they may be administered, the dosage being adjusted for the relative potency of the particular steroid and the requirements of the patient.

The final products of this invention may be prepared by the processes of this invention, which entail a number of steps starting with the compounds represented by the following formulae methyl l4-methyl-A-nor-A -androstene- 1 1fl-ol-3, l5-dione- 17,8-carboxylate.

The process of the instant invention may be represented by the following equations, wherein X, R, R and Z are as hereinbefore defined:

COOB

as Log;

COOB R m o to Dog CHNZ wh my;

w tog CHzZ CH3 CH3 XV ZzH RzH: RzOH XXIII ZIhaIide XVI Z:OH RIH; RzOH XXIV Z:H

XXII ZICHaCOO R & R' .0:

In the first step of the process of this invention, the ll-substituted A-nor-A -androstenes (Compounds A) and the A-nor-A -androstadiene (Compounds B) starting materials are reacted with a diazoalkane (e.g. diazomethane) in the presence of a metal halide (e.g. aluminum chloride) to yield the respective pyrazoline derivatives thereof (Compounds C and D) which are new compounds of this invention.

Compounds C and D may then be heated at temperatures above their respective melting points to yield the respective 6-methyl-A -androstene (Compounds E) and the 6-methyl-A )-androstadienes (Compounds P), which are also new compounds of this invention.

Compounds E and F may then be treated with an acid halide, for example, oxalyl chloride, to obtain the corresponding ll-substituted 6-methyl-A-nor-A -androstene-l7-carboxylic acid halides (Compounds G) and the 6-methyl-A-nor A androstadiene 17 carboxylic acid chlorides (Compounds H) respectively, which are also new compounds of this invention.

These acid chloride compounds (Compounds G and H) are then converted to their respective diazoketone-6- methyl-A-nor-A -pregnenes (Compounds 1) and diazoketone 6-methyl-A-nor-A -pregnadienes (Compounds K), which are also new compounds of this invention, by treatment with an ethereal solution of diazomethane.

In order to obtain the final products of this invention which are oxygenated in the 2l-p0sition (i.e. Z is acyloxy or hydroxy). Compounds J and K are treated at elevated temperature with a fatty acid, for example, acetic, propionic or butyric acid, to yield the 2l-esters of ll-substituted-6-methyl-A-nor-A -pregnenes (Compounds L) and 6-methyl-A-nor-A -pregnadienes (Compounds M), which are also new compounds of this invention. Alternatively, Compounds L and M (wherein Z is acyloxy) may be obtained by first treating Compounds J and K with a hydrohalide, for example, hydrochloric acid, to yield the 21-halogenated-A-nor-pregnenes (Compounds L and M, wherein Z is halide), which are also new compounds of this invention, and then substituting the 2l-halide-A-norpregnenes as by treatment with potassium iodide and potassium acetate to yield the respective 21-acyloxy-A-n0rpregnenes (Compounds L and M). To obtain the 2l-hydroxy-A-nor-pregnene compounds of this invention (Compounds L and M, wherein Z is hydroxy), the 21- acyloxy compounds are treated with a base, such as potassium carbonate. The 2l-hydroxy-6-methyl-A-nor-pregnenes (Compounds L and M, wherein Z is hydroxy) are also new compounds of this invention.

To obtain the final compounds of this invention, which are not oxygenated in the 2l-position (i.e. wherein Z is hydrogen or halogen), Compounds 1 and K are first treated with hydriodic acid to yield the 2l-unsubstituted- A-nor-pregnenes (Compounds L and M, wherein Z is hydrogen), which are also new compounds of this invention.

The 21-halogenated compounds are obtained as set forth hereinabove, i.e., by treatment of Compounds J and K with a hydrohalide, e.g., hydrochloric acid. It should be noted that when the 15-keto starting materials are employed in the practice of this invention, the final products thereof and the intermediates produced thereby Methyl 14-methyl-5,6-pyrazolino-A-norandrostane- 3 ,11-dione-17fl-carboxylate (II) To a suspension of 50 mg. of finely powdered methyl 14 methyl A nor-A -androstene-3-,ll-dione-17p-carboxylate (I) in 30 ml. of ethereal diazomethane solution is added at room temperature, in portions, a total of 20 mg. of aluminum chloride which had been aged by leaving it exposed to the atmosphere for 5-10 minutes. The total reaction time is one hour and thirty minutes. The excess diazomethane is then destroyed by the addition of two drops of glacial acetic. The mixture is washed with water and the ether extract evaporated to dryness in vacuo. The resulting residual mixture is purified by preparative thin layer chromatography on activity V neutral alumina using chloroform as the moving phase. Two zones are obtained, designated as A and B. The elution of zone A furnishes after concentration 21 mg. of material, M.P. ZOO-201, which is identified as starting material. Elution of zone B furnishes after crystallization from methanol 9 mg. of methyl 14-methyl-5,6-pyrazolino-A- norandrostane-3,11-dione-l7B-carboxylate which melts with decomposition at 176l78; [u] +360 (c. 0.28 in chloroform);

Affifi; 5.79, 5.87, 6.53;;

Analysis.-Calcd. for C H O N (386.48) (percent): C, 68.37; H, 7.82. Found (percent): C, 68.43; H, 7.81.

EXAMPLE 2 Methyl 14-methyl-5,6-pyrazolino-A-nor-A androstene-3-one-17fi-carboxylate Following the procedure set forth in Example 1 but substituting an equivalent amount of methyl 14-methyl-A- nor A androstadiene 3 one-17f3carboxylate for methyl 14 methyl A-nor-A -androstene-3,11-dione-l7/icarboxylate, there is obtained methyl 14-methyl-5,6- pyrazolino A nor A -androstene-3-one-17,B-carboxylate.

EXAMPLE 3 Methyl 14-methyl-5,6-pyrazolino-A-norandrostane- 1 fl-ol-3-one-17fi-carboxylate Following the procedure set forth in Example 1, but substituting an equivalent amount of methyl 14-methyl- A nor A androstene-l1,3-01-3-0ne-l7l3-carboxylate for methyl 14 methyl A-nor-A -androstene-3,l1-dione-l7,8- carboxylate, there is obtained methyl 14-methyl-5,6- pyrazolino A norandrostane-l1p-ol-3-one-17fl-carboxylate.

EXAMPLE 4 Methyl 6,14-dimethyl-A-nor-A -androstene- 3,11-dione-17B-carboxylate (III) Five mg. of methyl l4-methyl-5,6-pyrazo1ino-A-norandrostane-3,11-dione-7/3-carboxylate (II) was placed into an evacuated tube and heated in a bath at a temperature of 150-170. The contents of the tube melts and sublimed to colder portions. The tube is then cooled, the bottom out off and the sublimate recrystallized from methanol. The

pure methyl 6,14 dimethyl A-nor-A -androstene-3,l1- dione-l7,B-carboxylate (III) melts at 172-174";

xttgi 255,. (=s,600 m... 5.75, 5.86, 6.10,. EXAMPLE 5 Methyl 6,14-dimethyl-A-nor-A -androstadiene- 3-one-17B carboxylate Following the procedure set forth in Example 4, but substituting an equivalent amount of methyl 14-methyl- 5,6 pyrazolino A-nor-A -androstene-17/3-carboxylate for methyl 14 methyl 5,6-pyrazolino-A-norandrostane- 3,11-dione-17B-carboxylate, there is obtained methyl 6,14- dimethyl A-nor-A -androstadiene-3-one-17fl-carboxylate.

EXAMPLE 6 Methyl 6,l4-dimethyl-A-nor-A -androstene- 1lfi-ol-3-one-N B-carboxylate Following the procedure set forth in Example 4, but substituting an equivalent amount of methyl l4-methyl- 5,6 pyrazoline A nor-A -androstene-1lfi-ol-one-17ficarboxylate for methyl 14-methyl-A-nor-A -androstene- 3,20-dione-Nil-carboxylate, there is obtained methyl 6,14- dimethyl A-nor-A -androstene-llfl-ol-3-one-l713-carboxylate.

EXAMPLE 7 6,14-dimethyl-A-nor-A -androstene- 3,1 1-dione-l7fi-carboxylic acid To a mixture of KOH in methanol and water, which has been refluxed for 10 minutes and cooled under a blanket of helium is added methyl 6,14-dimethyl-A-nor- A -androstene-3,l1-dione-17fl-carboxylate and the resulting solution is refluxed under a blanket of helium. The mixture is then cooled and after the addition of glacial acetic acid is diluted with water. After the removal of the bulk of the methanol in vacuo the 6,14-dimethyl-A-nor- A -androstene-3,l1-dione-l7B-carboxylic acid crystallizes and is filtered and washed with water.

EXAMPLE 8 6,14-dimethyl-A-nor-A -androstadiene-3-one- 17p-carboxylic acid Following the procedure set forth in Example 7 but substituting an equivalent amount of methyl 6,14-dimethyl- A-nor-A -androstadiene 3-one-17B-carboxylate for methyl 6,14-dimethyl-A nor A -androstene-3,11-dione- 17fi-carboxylate, there is obtained 6,14-dimethyl-A-nor- A -androstadiene-S-one-17B-carboxylic acid.

EXAMPLE 9 6,14-dimethyl-A-nor-A -androstene-1 1 [3-01-3-one- 19,8-carboxylic acid Following the procedure in Example 7 but substituting an equivalent amount of methyl 6,14-dimethyl-A-nor- A -androstene-11,8-01-3-one-NIB-carboxylate for methyl 6,l4-dimethyl-A-nor-A -androstene-3,l1-dione-l7fl carboxylate, there is obtained 6,14-dimethyl-A-nor-A -androstene-l1fi-ol-3-one-19fl-carboxylic acid.

EXAMPLE 10 6,14-dimethyl-A-nor-A -androstene-3 ,1 1-dione-17pcarboxylic acid chloride To a suspension of vacuum dried 6,14-dimethyl-A-nor- A -androstene-3,ll-dione-17{3-carboxylic acid in anhydrous benzene is added with stirring redistilled oxalyl chloride. After 30 minutes all the acid has dissolved and the solution is allowed to remain at room temperature for an additional 40 minutes. Upon the removal of the solvent in vacuo there remains a crystalline solid to which is added anhydrous benzene and then later removed again in vacuo, thus yielding 6,14-dimethyl-A-nor-A androstene-3,1l-dione-l7fl-carboxylic acid chloride.

7 EXAMPLE 11 6,14-dimethyl-A-nor-A -androstadiene-3-one- 17,3-carboxylic acid chloride Following the procedure set forth in Example 10 but substituting an equivalent amount of 6,14-dirnethyl- A-nor-A -androstadiene-3-one-17 8-carboxylic acid for 6,14-di1r1ethyl-A-nor-A androstene 3,11-dione-17fl-carboxylic acid there is obtained 6,14-dimethyl-A-nr-A androstadiene-3-one-17fl-carboxylic acid chloride.

EXAMPLE 12 6,14-dimethyl-A-nor-A -androstene-1 l [3-ol-3-0ne- 17B-carboxylic acid chloride Following the procedure set forth in Example but substituting an equivalent amount of 6,14-dimethyl-A-nor- A -androstene-11fl-ol-3-one-17/3-carboxylic acid for 6,14- dimethyl-A-nor-A -androstene-3,11 dione-17fl-carboxylic acid there is obtained 6,14-dimethyl-A-nor-A -androstene- 11p-ol-3-one-17,8-carboxylic acid chloride.

EXAMPLE 13 6,14-dimethyl-2 1-diazo-A-nor-A -pregnene- 3 ,11,20-trione A solution of 6,14-dimethyl-A-nor-A -androstene-3,11- dione-17,6-carboxylic acid chloride in anyhdrous benzene is added at 0 C. to a concentrated distilled solution of diazomethane in ether. The mixture is allowed to warm up to room temperature and after a total reaction time of 1 /2 hours it is filtered from fiocculent polyethylene and evaporated to dryness in vacuo. The resulting crystalline residue is recrystallized from methanol and furnishes 6,14-dimethyl-21-diazo-A nor A pregnene-3,11,20 trione.

EXAMPLE l4 6,14-dimethyl-21-diazo-A-nor-A -pregnadiene- 3,20-dione Following the procedure set forth in Example 13 but substituting an equivalent amount of 6,14-dimethyl-A-nor- A -androstadiene-3-one-17,6-carboxylic acid chloride for 6,14-dirnethyl-A-nor-A androstene-3,11-dione-17ficarboxylic acid chloride there is obtained 6,14-dimethyl- 2l-diazo-A-nor-A -pregnadiene-3,20-dione.

EXAMPLE 15 6,l4-di1nethyl-21-diazo-A-nor-A -pregnene-l1,8-01- 3,20-dione Following the procedure set forth in Example 13 but substituting an equivalent amount of 6,14-dimethyl-A- nor-A -androstene-11/3-ol-3-one-l7 3-carboxylic acid chloride for 6,l4-dimethyl-A-nor-A -androstene-3,ll-dione- 17 8-carboxylic acid chloride there is obtained 6,14-di methyl-21-diazo-A-nor-A -pregnene- 1 1,B-ol-3,20-dione.

EXAMPLE 16 6,14-dimethyl-21-chloro-A-nor-A -pregnene-3,1 1, -trione is substituted for the hydrogen chloride, 6,14-dimethyl- 21-iodo-A-nor-A -pregnene-3,l1,20-trione is obtained.

EXAMPLE l7 6,14-dimethyl-21-chloro-A-nor-A -pregnadiene- 3 ,20-dione Following the procedure set forth in Example 16 but substituting an equivalent amount of 6,14-dimethyl-21' diazo-A-nor-A -pregnadiene-3,20-dione for 6,14-dimethyl-21-diazo-A-nor-A -pregnene-3,11,20-trione there is obtained 6,14-dimethyl-2l-chloro A-nor-A -preg' nadiene-3,20-dione.

EXAMPLE l8 6,l4-dimethyl-21-chloro-A-nor-A -pregnene-11,6-01- 3,20-dione Following the procedure set forth in Example 16 but substituting an equivalent amount of 6,14-dimethyl-21- diazo-A-nor-M-pregnene-11B-ol-3,20-dione for 6,14-di' methyl-21-diazo-A-nor-A pregnene-3,11,20-trione there is obtained 6,14-dimethyl-21-chloro-A-nor-A -pregnene-11,8 ol-3,20-dione.

EXAMPLE 19 6, 1 4-dimethyl-A-nor- A -p1'egnene-3 ,1 1,20-trione To a solution of 6,14-dimethyl-21-diazo-A-nor-A pregnene-3,1l,20-trione in chloroform is added under a blanket of carbon dioxide freshly distilled aqueous hydriodic acid. The mixture is thoroughly mixed by shaking for 3 minutes at room temperature, poured into water and chloroform and the chloroform solution extracted with dilute sodium bicarbonate with the addition of a small amount of sodium bisulfite. The chloroform extract is then washed with water, dried over sodium sulfate and evaporated to dryness in vacuo and the residue crystallized from methanol to yield 6,14-dimethyl-A-nor-A pregnene-3,1 1,20-trione.

EXAMPLE 20 6,14-dimethyl-A-nor-A pregnadiene 3,20-dione Following the procedure set forth in Example 19 but substituting 6,14-dimethyl 21-diazo-A-nor-A -pregnadiene-3,20-dione for 6,14-dimethyl-21-diazo-A-nor-A pregnene-3,1l,20-trione yields 6,14 dimethyl-A-nor- A -pregnadiene-3,2O-dione.

EXAMPLE 21 6,l4-dimethyI-A-nor-A -pregnene--01-3 ,ZO-di one Following the procedure set forth in Example 19 but substituting an equivalent amount of 6,14-dimethyl-21- diazo-A-nor-A -pregnene-11fl-ol-3,20 dione for 6,14-dimethyl-21-diazo-A-nor-Mpregnene 3,11,20-trione yields 6,l4-dimethyl-A-nor-A -pregnene-11,8-ol-3,20-dione.

EXAMPLE 22 6, l4-dimethyl-A-nor-A -pregnene-21-0l-3,1 1,20-

trione-Z l -acetate A solution of 6,l4-dimethyl-2 l-diazo-A-nor-A -pregnone-3,11,20-trione in glacial acetic acid is heated on the steam bath for /2 hour. Water and chloroform are added and the resulting chloroform extract washed with sodium bicarbonate and water, dried over sodium sulfate and the solvent evaporated to dryness in vacuo. The residual crystals obtained after recrystallization from methanol yield 6,l4-dimethyl-A-nor-M-pregnene 21 ol3,ll,20- trione-2l-acetate.

Similarly, substituting propionic acid, butyric acid or other fatty acids for the acetic acid of Example 22 there are obtained the corresponding propionic, butyric and other esters of 6,14-dimethyl-A-nor-M-pregnene-2l-ol- 3,11,20-trione.

9 EXAMPLE 23 6,14-dimethyl-A-nor-A -pregnadiene-21-ol- 3,20-dione-21-acetate Following the procedure set forth in Example 22 but 5 substituting 6,14-dirnethyl-21-diazo-A-nor A -pregnadiene-3,20-dione for 6,14-dirnethyl 21-diazo-A-nor- A -pregnene-3,11,2O-trione yields 6,14 dimethyl-A-nor- A -pregnadiene-21-01-3,20-dione-2l-acetate.

EXAMPLE 24 6,14-dimethy1-A-nor-A -pregnene-1 1,6,21-dio1- 3,20-dione-21-acetate Following the procedure set forth in Example 22 but substituting 6,14-dimethyl-21 diazo-A-nor-A -pregnene- 11/3-ol-3,20-dione for 6,14 dimethyl-Zl=diazo-A-nor-A pregnene-3,l1,20-trione yields 6,14 dimethyl-A-nor-A pregnene-l 1,8,21-diol-3,20-dione2l-acetate.

EXAMPLE 25 6, 14-dimethyl-A-nor-M-pregnene-2 l-ol- 3,11,20-trione 6,14-dimethyI-A-nOr-A -pregnene-2l-ol- 3,20-dione Following the procedure set forth in Example 25 but substituting; 6,14-dimethyl-A-nor-A -pregnadiene 21- ol-3,20dione-21-acetate for 6,14-dimethyl-A-nor-M-pregnene-21-o1-3,11,20-trione-21-acetate there is obtained 6,14-

dimethyl-A-nor-A l 1 -pregnene-21-ol-3,20-dione.

10 EXAMPLE 27 6,14-dimethyl-A-nor-A -pregnene- 1 1,8,21-diol- 3,20-dione Following the procedure set forth in Example 25 but substituting 6, 14-dimethyl-A-nor-A -pregnene-1 1,3,21-diol- 3,20-dione 21-acetate for 6,14 dimethyl-A-nor-M-pregnene-21-ol-3,11,20-trione-2l-acetate there is obtained 6,14- dimethyl-A-nor-A -pregnene-11fl,21-diol-3 ,20-dione.

The invention may be variously otherwise embodied within the scope of the appended claim.

What is claimed is:

1. A compound selected from the group consisting of steroids of the formulae:

wherein A is halogen; R is hydrogen; R is hydroxy; and together R and R is oxo(O=); and X is lower alkyl.

References Cited UNITED STATES PATENTS 3,170,919 2/1969 Fried 260-2395 LORRAINE A. WEINBERGER, Primary Examiner E. J. GLEIMAN, Assistant Examiner 

